The long-term goal of this project is to reduce or reverse the oral complications of highly active antiretroviral therapy (HAART) in patients infected with the human immunodeficiency virus (HIV). Although the oral manifestations of HIV infection have significantly decreased after the introduction of HAART, several adverse effects have also been reported in the oral mucosa, including recurrent oral ulceration, epithelial atrophy, erythema multiforme, epithelial desquamation, eruptive chielitis, and multiple oral warts. The purpose of the current application is to elucidate the effects of telomerase inhibition by reverse transcriptase inhibitors (RTIs) in mediating the side effects of HAART. Telomerase is a cellular reverse transcriptase with at least two distinct biological functions in (1) synthesis of telomere DNA and (2) maintenance of genome integrity. Our laboratory found remarkably high level of telomerase activity in normal human oral keratinocytes (NHOK) derived from oral epithelium. Telomerase activity in NHOK is specifically associated with actively proliferating cells and is completely lost during cellular senescence. Importantly, telomerase activity can be effectively inhibited by several RTIs commonly used as HAART. The central hypothesis of this proposal is that telomerase inhibition in NHOK by RTIs is responsible for the diminution of regenerative capacity of the oral epithelium and adverse oral mucosal complications associated with long-term administration of HAART in HIV+ patients. To test our hypothesis, we propose three Specific Aims: (1) to determine the telomerase activity, telomeric status, and cellular phenotypic alterations in NHOK exposed to RTIs in vitro and in cells derived from HIV+ patients with and without HAART;(2) to determine the effects of RTI/HAART on the DNA repair activities, mutation frequency, and genetic integrity in NHOK;and (3) to investigate the effects of AZT on phenotypic alterations in NHOK expressing exogenous telomerase or acquiring enhanced replication potential.
The aims 1 and 2 will investigate the detailed phenotypic and genetic effects of RTI/HAART in oral epithelium.
In aim 3, we will determine whether augmenting cellular telomerase activity and/or """"""""priming"""""""" the cells with enhanced replicative potential can prevent the adverse phenotypic effects of AZT. The outcome of this project will be used for prevention and management of oral manifestations of HIV infection and the acquired immunodeficiency syndrome (AIDS) by reducing the negative effects of HAART.
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